[go: up one dir, main page]

EP0124476A1 - Carboxamides, procédé pour leur préparation et préparations pharmaceutiques les contenant - Google Patents

Carboxamides, procédé pour leur préparation et préparations pharmaceutiques les contenant Download PDF

Info

Publication number
EP0124476A1
EP0124476A1 EP84810109A EP84810109A EP0124476A1 EP 0124476 A1 EP0124476 A1 EP 0124476A1 EP 84810109 A EP84810109 A EP 84810109A EP 84810109 A EP84810109 A EP 84810109A EP 0124476 A1 EP0124476 A1 EP 0124476A1
Authority
EP
European Patent Office
Prior art keywords
halogen
formula
methoxy
ethyl
piperidinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP84810109A
Other languages
German (de)
English (en)
Other versions
EP0124476B1 (fr
Inventor
Angelo Dr. Storni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy AG filed Critical Ciba Geigy AG
Priority to AT84810109T priority Critical patent/ATE35257T1/de
Publication of EP0124476A1 publication Critical patent/EP0124476A1/fr
Application granted granted Critical
Publication of EP0124476B1 publication Critical patent/EP0124476B1/fr
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/16—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms
    • C07D203/18—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms by carboxylic acids, or by sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms

Definitions

  • the invention relates to pharmaceutical preparations containing carboxamides, in particular N- (piperidinyl-alkyl) -carboxamides and their salts, processes for their preparation, the use of these compounds, new N- (piperidinyl-alkyl) -carboxamides and processes for their preparation.
  • a monocyclic arylene radical Ar 1 is primarily unsubstituted or substituted one or more times in addition to the radical R and the CO group, phenylene, in particular 1,2-phenylene, and also 1,3- or 1,4-phenylene.
  • a monocyclic heteroarylene radical Ar 1 is, for example, a monocyclic azaarylene bonded via a carbon atom with up to and with 3 nitrogen atoms, primarily unsubstituted or mono- or polysubstituted pyridylene, especially those in which the carbamoyl group in position 3 and the radical R is bonded in position 2 of the pyridylene ring, such as 2,3-pyridylene, and further 3,2-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-pyridylene.
  • the carbamoyl group is preferably bonded to a carbon atom adjacent to the radical R.
  • Additional substituents of the arylene or heteroarylene radicals mentioned above include, for example aliphatic radicals, hydroxy, hydroxy, acyl, nitro, carboxy, esterified with an organic carboxylic acid or with an inorganic acid or etherified with an aliphatic alcohol, e.g. with an aliphatic alcohol, esterified carboxy, cyano, unsubstituted or, e.g. by an aliphatic radical, mono- or disubstituted carbamoyl, unsubstituted or, e.g. by an aliphatic radical, mono- or disubstituted amino, unsubstituted or, e.g.
  • an aliphatic radical mono- or disubstituted sulfamoyl, or, e.g. substituted by an aliphatic radical, mercapto and / or, e.g. by an aliphatic radical, substituted sulfinyl or sulfonyl.
  • Aliphatic radicals are primarily lower alkyl, further e.g. Lower alkenyl or lower alkadienyl, or halogen lower alkyl.
  • hydroxy esterified with an organic carboxylic acid is especially lower alkanoyloxy and hydroxy esterified with an inorganic acid is primarily halogen, while hydroxy etherified with an aliphatic alcohol is especially lower alkoxy, furthermore e.g. Niederalkenyloxy, or halogen lower alkoxy means.
  • Acyl is derived in particular from an organic carboxylic acid and is primarily lower alkanoyl. Carboxy esterified with an aliphatic alcohol is in particular lower alkoxycarbonyl. In carbamoyl or amino or sulfamoyl mono- or disubstituted by an aliphatic radical, the respective group is primarily mono- or disubstituted by lower alkyl.
  • Such residues are, for example, N-lower alkyl or N, N-di-lower alkyl carbamoyl, N-lower alkyl or N, N-di-lower alkylamino or N-lower alkyl or N, N-di-lower alkyl sulfamoyl.
  • Tuated mercapto primarily means lower alkylthio or halogenated lower alkylthio, while sulfinyl or sulfonyl substituted by an aliphatic radical is primarily understood to mean lower alkane or halogenated lower alkane sulfinyl or sulfonyl.
  • An alkylene group alk which separates the two N atoms by at least two C atoms is primarily corresponding alkylene which separates the two N atoms by 2 to 3 C atoms, for example with 2 to and with 7, in particular 2 or 3, C. -Atoms.
  • a ketalized carbonyl group X is e.g. ketalized with a mono- or dihydric aliphatic alcohol and primarily means di-lower alkoxy or lower alkylenedioxy-methylene.
  • Hydroxymethylene X esterified with an organic carboxylic acid is primarily lower alkanoyloxymethylene.
  • a monocyclic aryl radical Ar2 primarily represents an unsubstituted or mono- or polysubstituted phenyl radical, while a monocyclic heteroaryl radical Ar 2 is, for example, a monocyclic monooxa, monoaza or monothiaaryl radical, primarily unsubstituted or mono- or polysubstituted furyl, pyridyl or Thienyl means.
  • Suitable substituents for aryl or heteroaryl radicals Ar 2 are those mentioned for Ar 1 , primarily halogen and also lower alkoxy.
  • lower means that correspondingly designated organic groups or compounds preferably contain up to and with 7, especially up to and with 4 carbon atoms.
  • Halogen is especially halogen with atom numbers up to and including 35, such as fluorine, chlorine or bromine, and also includes iodine.
  • Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and further includes corresponding pentyloxy, hexyloxy and heptyloxy groups.
  • Lower alkenyloxy is e.g. Allyloxy or But-2-en- or But-3-enyl-oxy.
  • Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and also includes corresponding pentyl, hexyl and heptyl radicals.
  • Lower alkenyl is e.g. 2-propenyl or 1-, 2- or 3-butenyl and lower alkadienyl e.g. Butadien-1,3-yl.
  • Halogen lower alkyl is e.g. Trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl or chloromethyl.
  • Lower alkanoyloxy is e.g. Acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.
  • Halogen lower alkoxy is e.g. Difluoromethoxy or 1,1,2-trifluoro-2-chloroethoxy.
  • Lower alkanoyl is e.g. Formyl, acetyl, propionyl, butyryl, isobutyryl or pivaloyl.
  • Lower alkoxycarbonyl is e.g. Methoxy, ethoxy, propyloxy or pivalyloxy carbonyl.
  • N-lower alkyl carbamoyl is, for example, N-methyl, N-ethyl, N- (n-propyl) or N-isopropyl-carbamoyl
  • N, N-di-lower alkyl-carbamoyl is, for example, N, N-dimethl or N, N-Diethyl-carbamoyl means.
  • N-lower alkyl-amino is, for example, N-methyl-, N-ethyl-, N- (n-propyl) - and N-isopropyl-amino
  • N, N-di-lower alkyl-amino is for example N, N-dimethyl- or N, Represents N-diethylamino.
  • N-lower alkyl sulfamoyl is e.g. N-methyl or N-ethyl sulfamoyl and N, N-di-lower alkyl sulfamoyl e.g. N, N-dimethyl or N, N-diethyl sulfamoyl.
  • Lower alkylthio is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butylthio.
  • Halogen lower alkylthio is e.g. Chloromethyl, trifluoromethyl or 1,1,2-trifluoro-2-chloroethylthio.
  • Lower alkanesulfinyl or sulfonyl is e.g. Methane, ethane, n-propane or isopropane sulfinyl or sulfonyl.
  • Halogen lower alkanesulfinyl or sulfonyl is e.g. Chloromethane, trifluoromethane or 1,1,2-trifluoro-2-chloroethane sulfinyl or sulfonyl.
  • 2- to 3-membered alkylene with 2 to 7, especially 2 to 3, C atoms is e.g. Ethylene or 1,3-propylene, also 1,2-propylene, and 2-methyl-1,2-propylene.
  • Lower alkylenedioxy is e.g. Ethylenedioxy or 1,3-propylenedioxy.
  • Thienyl is e.g. 2-thienyl, further 3-thienyl and furyl e.g. 2-furyl, furthermore 3-furyl, while pyridyl e.g. 2- or 3-pyridyl, furthermore 4-pyridyl.
  • Salts of compounds of formula (I) are preferably pharmaceutically acceptable salts. Because of their basic group (s), compounds of the formula (I) can form, for example, acid addition salts. These are, for example, with strong inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acids or hydrohalic acids, or with strong organic acids, such as lower alkane carboxylic acids, for example acetic acid, optionally unsaturated dicarboxylic acids, for example oxalic, malonic, maleic or fumaric acid, hydroxycarboxylic acids, for example tartaric acid or citric acid, or arylcarboxylic acids, for example benzoic acid, educated.
  • strong inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acids or hydrohalic acids
  • strong organic acids such as lower alkane carboxylic acids, for example acetic acid, optionally unsaturated dicarboxylic acids, for example oxalic, malonic, maleic or fumaric acid, hydroxy
  • acid addition salts are, for example, sulfonic acids, such as lower alkanesulfonic acids, for example methanesulfonic acid, or optionally substituted benzenesulfonic acids, for example p-toluenesulfonic acid. Salts which are unsuitable for pharmaceutical uses are also included, since these can be used, for example, for the isolation or purification of corresponding free compounds of the formula (I) and their pharmaceutically acceptable salts.
  • sulfonic acids such as lower alkanesulfonic acids, for example methanesulfonic acid
  • benzenesulfonic acids for example p-toluenesulfonic acid.
  • the compounds according to the invention can exist as structural isomers.
  • Compounds of formula (I) have chiral carbon atoms, e.g. if X of formula (I) is free or hydroxymethylene esterified with an organic carboxylic acid, they can e.g. as pure enantiomers or mixtures of enantiomers, such as racemates, and, if at least one further chiral center is present, as diastereomers or mixtures of diastereomers.
  • the compounds of the formula (I) and their pharmaceutically usable salts can be used, for example, as medicaments, for example as antipsychotics, or in a process for the prophylactic or therapeutic treatment of the human and also of the animal body.
  • the compounds of the formula (I) in particular have valuable pharmacological properties. Above all, they have a pronounced antipsychotic effect.
  • the compounds antagonize the formula (I) as investigations analog B. Costall et al., B rain Research 123, 89-111 (1977), show mg from a dose of about 1 / kg when administered intraperitoneally, the conditional by amphetamine stereotypy the rat.
  • the compounds of the formula (I) have a pronounced antidopaminergic activity. This is determined by the formation rate of metabolites of the neurotransmitter dopamine (DA), since the increase in DA turnover is considered a measure of the dopamine receptor blockade.
  • DA neurotransmitter dopamine
  • the DA receptor blockade by compounds of the formula (I) can also be determined directly by in-vivo inhibition of the [ 3 H] spiperone binding in the hippocampus region of the rat.
  • a strong dopamine receptor blocking effect was found in a dose range from about 0.01 to about 100 mg / kg after intraperitoneal administration to the rat.
  • compounds of formula (I) and their salts e.g. due to their strong antidopaminergic activity, for example as antipsychotics, in particular with an effect on the hippocampal dopaminergic system.
  • the fact that little or no extrapyramidal side effects are observed when using compounds of the formula (I) is particularly advantageous.
  • the invention relates in particular to pharmaceutical preparations containing compounds of the formula (I), in which R is hydroxyl, lower alkoxy, lower alkenyloxy or halogen, Ar is in each case unsubstituted or one or more times by lower alkyl, lower alkenyl, lower alkadienyl, halogen-lower alkyl, hydroxy, Lower alkanoyloxy, halogen, lower alkoxy, lower alkenyloxy, halogen lower alkoxy, lower alkanoyl, nitro, cyano, carbamoyl, N-lower alkyl-carbamoyl, N, N-diniederalkyl-carbamoyl, carboxy, lower alkoxycarbonyl, amino, N-lower alkyl-amino, N, N-diniederalkyl- amino, sulfamoyl, N-lower alkylsulfamoyl, N, N-di-lower alkylsulf
  • the invention relates in particular to pharmaceutical preparations containing compounds of the formula (I) in which R is hydroxyl, lower alkoxy, lower alkenyloxy or halogen, Ar is in each case unsubstituted or one or more times by lower alkyl, lower alkenyl, lower alkadienyl, halo-lower alkyl, hydroxy, lower alkanoyloxy, halogen , Lower alkoxy, lower alkenyloxy, halogen-lower alkoxy, lower alkanoyl, nitro, cyano, carbamoyl, N-lower alkyl-carbamoyl, N, N-di-lower alkyl-carbamoyl, amino, N-lower alkyl-amino, N, N-di-lower alkyl-amino, sulfamoyl, N-lower alkyl -sulfamoyl, N, N-di-lower alkyl-amin
  • the invention relates in particular to pharmaceutical preparations containing compounds of the formula (I) in which R is lower alkoxy, for example having up to and with 4 carbon atoms, such as methoxy, Ar 1 for unsubstituted or in each case one or more times by lower alkyl, for example with up to and including 4 C-atoms, such as methyl, halo-lower alkyl, for example, having up to and including 4 carbon - atoms, such as trifluoromethyl, halogen, for example with an atomic number of up to and including 35, such as fluorine, chlorine or bromine, lower alkoxy such as with up to and including 4 carbon atoms, such as methoxy, cyano, carbamoyl, amino, N-lower alkylamino, for example with up to and with 4 carbon atoms, such as N-methylamino, N, N-di-lower alkylamino, for example each with up to and with 4 carbon atoms in the Lower alkyl part,
  • the invention relates in particular to pharmaceutical preparations containing compounds of the formula (I) in which, on the one hand, R denotes lower alkoxy, in particular with up to and with 4 carbon atoms, such as methoxy, or halogen, in particular with an atom number up to and including 35, such as fluorine, and Ar 1 for unsubstituted or additionally one or more times by lower alkyl, in particular with up to and with 4 carbon atoms, such as methyl, halogen-lower alkyl, in particular with atom number up to and with 35 and with up to and with 4 carbon atoms, such as trifluoromethyl, hydroxy, halogen , in particular with atom numbers up to and including 35, such as bromine, lower alkoxy, in particular with up to and with 4 carbon atoms, such as methoxy, cyano, carbamoyl, lower alkoxycarbonyl, in particular with 2 to and with 5 carbon atoms, such as methoxycarbonyl, amino, and lower al
  • the invention relates above all to pharmaceutical preparations containing compounds of the formula (I) in which R is lower alkoxy, for example with up to and with 4 carbon atoms, such as methoxy, Ar 1 on the one hand for an unsubstituted or one or more additions by halogen-lower alkyl, for example with up to and with 4 C atoms, such as trifluoromethyl, halogen, for example with an atom number up to and with 35, such as fluorine, chlorine or bromine, lower alkoxy, for example with up to and with 4 C atoms, such as methoxy, cyano, carbamoyl, N.
  • R is lower alkoxy
  • 4 carbon atoms such as methoxy
  • Ar 1 on the one hand for an unsubstituted or one or more additions by halogen-lower alkyl, for example with up to and with 4 C atoms, such as trifluoromethyl, halogen, for example with an atom number up to and with 35,
  • alkylamino for example with up to and with 4 carbon atoms, such as methylamino, sulfamoyl, N, N-di-lower-alkyl sulfamoyl, for example with up to and with 4 carbon atoms, such as dimethylsulfamoyl, halogenated lower alkylthio, for example with up to and with 4 carbon atoms , such as trifluoromethylthio, and / or halogen-lower alkane-sulfonyl, for example with up to and with 4 carbon atoms, such as trifluoromethanesulfonyl, substituted phenyl radical, on the other hand for one or more additional lower alkoxy, for example with up to and with 4 carbon atoms, such as methoxy , and or Halogen, for example with atom number up to and including 35, such as chlorine, substituted pyridylene radical, such as 3,2-pyridylene,
  • the invention relates above all to pharmaceutical preparations containing compounds of the formula (I), in which the grouping R-Ar 1 for the structural element of the formula is in which one of the radicals R a and R c is the radical R and this lower alkoxy, in particular with up to and with 4 carbon atoms, such as methoxy, or halogen, in particular with atom number up to and including 35, such as fluorine, and the other Hydrogen, lower alkyl, in particular with up to and with 4 carbon atoms, such as methyl, halogen, in particular with atom number up to and with 35, such as bromine, or lower alkylamino, in particular special with up to and with 4 carbon atoms, such as methylamino, and the radicals R b , R d and R e independently of one another for hydrogen, lower alkyl, in particular with up to and with 4 carbon atoms, such as methyl, halogeno lower alkyl, in particular with Atom numbers up to and with 35 and with up to and
  • the invention relates above all to pharmaceutical preparations containing compounds of the formula (I), in which the grouping R-Ar l - for the structural element of the formula Ib is in which, on the one hand, the radical R a denotes the radical R and this lower alkoxy with up to and with 4 carbon atoms, such as methoxy, and R is hydrogen, halogen with an atomic number up to and including 35, such as fluorine, or lower alkylamino with up to and with 4 C atoms, such as methylamino, or R a is hydrogen and R c is the radical R and this lower alkoxy is up to and with 4 C atoms, or in which the radical R c is the radical R and this represents halogen with atomic number up to and including 35, such as fluorine, and R a represents hydrogen or halogen with atomic number up to and including 35, such as bromine, and one of the radicals R b and R represents hydrogen, lower alkyl with up to and with 4 C- Atoms such
  • the invention relates in particular to pharmaceutical preparations containing compounds of the formula (I), in which Ar 1, on the one hand, is repeated one or more times by halogen with an atom number up to and including 35, such as chlorine, cyano and / or N-lower alkylamino with up to 4 C -Atoms in the lower alkyl part, such as methylamino, substituted phenylene, such as 1,2-phenylene, or on the other hand pyridylene, such as 3,2-pyridy len, represents, and each R lower alkoxy up to and with 4 carbon atoms.
  • halogen with an atom number up to and including 35, such as chlorine, cyano and / or N-lower alkylamino with up to 4 C -Atoms in the lower alkyl part, such as methylamino, substituted phenylene, such as 1,2-phenylene, or on the other hand pyridylene, such as 3,2-pyridy len,
  • R, Ar 1 , alk, X and Ar 2 have the meanings given, with the proviso that the grouping R-Ar 1 - is different from the rest of the formula (Ia), in which R 1 is selected from the group consisting of halogen with atomic numbers up to and with 35 and lower alkoxy with up to and with 4 C atoms, n represents an integer from 1 to and with 3, and Z lower alkylamine with up to and with 4 C- Represents atoms, and processes for their preparation.
  • the invention relates primarily to pharmaceutical preparations containing compounds of the formula (I) in which R is lower alkoxy with up to and with 4 carbon atoms, such as methoxy, Ar 1 for additionally substituted by cyano, in particular in the p-position to R. 1,2-phenylene, alk is ethylene, X is carbonyl, and Ar 2 is phenyl substituted by halogen with atom numbers up to and including 35, such as fluorine, in particular in the p-position, and their salts, the use of these compounds and their salts, new compounds of the formula (I) and their salts, in which R, Ar 1 , alk, X and Ar have the meanings indicated, and processes for their preparation.
  • R is lower alkoxy with up to and with 4 carbon atoms, such as methoxy
  • Ar 1 for additionally substituted by cyano, in particular in the p-position to R.
  • 1,2-phenylene alk is ethylene
  • X is carbonyl
  • Ar 2 is phen
  • the invention relates primarily to pharmaceutical preparations containing compounds of the formula (I), in which the grouping R-Ar l - stands for the structural element of the formula Ib in which, on the one hand, R represents the radical R and this lower alkoxy with up to and with 4 C- Atoms such as methoxy means R b and R are hydrogen, R c is lower alkylamino with up to and with 4 C atoms, such as methylamino, and R d is halogen with atomic numbers up to and including 35, such as chlorine, or R c is hydrogen or Halogen with atomic numbers up to and including 35, such as chlorine, and R d is cyano, or in which, on the other hand, R a , R d and R e are hydrogen, R b halogen with atomic numbers up to and including 35, such as bromine, and R c den Radical R and this lower alkoxy with up to and with 4 C atoms, such as methoxy, and each alk represents ethylene, X
  • the invention relates primarily to pharmaceutical preparations containing compounds of the formula (I), in which the grouping R-Ar 1 - stands for the structural element of the formula Ib in which one of the radicals R a and R b is hydrogen or halogen with an atomic number to and with 35, such as bromine, and the other being hydrogen, R represents the radical R and this halogen with atomic number up to and with 35, such as fluorine, and R d and R e are each hydrogen and alk is ethylene, X is carbonyl and Ar 2 is p-fluorophenyl, and their salts, the use of these compounds and their salts, new compounds of the formula (I) and their salts, in which R, Ar 1 , alk, X and Ar 2 have the meanings given, and Process for their production.
  • R-Ar 1 - stands for the structural element of the formula Ib in which one of the radicals R a and R b is hydrogen or halogen with an atomic number to and with 35, such as bro
  • the invention relates primarily to pharmaceutical preparations containing compounds of the formula I, in which the grouping R-Ar 1 - stands for the structural element of the formula Ib in which R a , R d and R are hydrogen, R b is hydrogen or halogen with an atomic number up to and with 35, such as bromine, and R c represents the radical R and this halogen with atomic number up to and including 35, such as fluorine, alk denotes ethylene, X represents carbonyl and Ar 2 represents 4-fluorophenyl, and their salts ,
  • R, Ar 1 , alk, X and Ar 2 have the meanings indicated, and processes for their preparation.
  • the invention relates primarily to pharmaceutical preparations containing compounds of the formula I, in which the grouping R-Ar 1 - stands for the structural element of the formula Ib, in which R a is the The radical R and this lower alkoxy with up to and with 4 carbon atoms, such as methoxy, R b , R c and R e are hydrogen and R d is cyano, alk is ethylene, X is carbonyl and Ar 2 is 4-fluorophenyl , and their salts, the use of these compounds and their salts, new compounds of the formula (I) and their salts, in which R, Ar 1 , alk, X and Ar 2 have the meanings indicated, and processes for their preparation.
  • R a is the The radical R and this lower alkoxy with up to and with 4 carbon atoms, such as methoxy, R b , R c and R e are hydrogen and R d is cyano, alk is ethylene, X is carbonyl and Ar 2 is 4-fluoroph
  • the invention relates in particular to the compounds mentioned in the examples, their salts and isomers.
  • Reactive functionally modified carboxy X 1 means, for example, esterified, primarily reactive esterified, carboxy, anhydridized carboxy or amidated carboxy.
  • Esterified carboxy is, for example, optionally substituted lower alkoxycarbonyl, such as ethoxycarbonyl, but preferably reactive esterified carboxy, for example optionally optionally, for example by lower alkoxy or optionally substituted carbamoyl, additionally activated vinyloxycarbonyl, such as 1-lower alkoxy-, for example 1-ethoxyvinyloxycarbonyl, or 2- (N-lower alkyl -carbamoyl) -, for example 2- (N-ethylcarbamoyl) -vinyloxycarbonyl, and optionally, for example by nitro, halogen, lower alkanesulfonyl or phenylazo, substituted phenoxy- or thiophenoxycarbonyl, such as 4-nitro-, 2,4,5-trichloro- , Pentachloro-, 4-methanesulfonyl-, 4-phenylazo-phenoxycarbonyl, thiophenoxy- or 4-nitrothioph
  • Reactive esterified carboxy can also be 1,1- or 1,3-disubstituted 2-isoureidocarbonyl, such as 1,1-di-lower alkyl, 1,1-diaryl or 1,1-diaryl-lower alkyl-2-isoureidocarbonyl, for example 1,1-diethyl -, 1,1-diphenyl- or 1,1-dibenzyl-2-isoureidocarbonyl, or 1,3-dicycloalkyl-, for example 1,3-dicyclohexyl-2-isoureido-carbonyl, or N-alkyleneaminooxycarbonyl, such as N-piperidinyl- oxycarbonyl, and N-imido-oxycarbonyl, for example N-succinimido-oxy- or N-phthalimido-oxycarbonyl.
  • 2-isoureidocarbonyl such as 1,1-di-lower alkyl,
  • Anhydrized carboxy is, for example, optionally branched lower alkoxycarbonyloxycarbonyl, such as ethoxy- or isobutyloxycarbonyloxycarbonyl, halocarbonyl, such as chlorocarbonyl, azidocarbonyl, halophosphoryloxycarbonyl, such as dichlorophosphoryloxycarbonyl, or optionally, e.g. lower alkanoyloxycarbonyl substituted by halogen or aryl, such as pivaloyloxy-, trifluoroacetyloxy- or phenylacetoxycarbonyl.
  • Anhydridized carboxy can also be symmetrically anhydridized carboxy of the formula R-Ar-CO-0-CO-.
  • Reactive amidated carboxy is, for example, optionally, e.g. lower alkyl, substituted 1-imidazolyl or 1-pyrazolylcarbonyl, such as 3,5-dimethyl-pyrazolylcarbonyl.
  • the process-specific condensation is carried out in a manner known per se, if necessary in the presence of an, in particular basic, condensation agent.
  • bases which can be used are alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines.
  • Examples include sodium hydroxide, hydride, amide, potassium tert-butoxide, carbonate, lithium triphenylmethylide, diisopropylamide, potassium 3- (aminopropyl) amide, bis (trimethylsilyl) amide, dimethylaminonaphthalene, di - or triethylamine, or ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyl trimethyl-ammonium hydroxide, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diaza-bicyclo [5.4.0] undec-7-ene (DBU), and also phosphines, such as triphenylphosphine , or halosilanes, such as tetrachlorosilane.
  • phosphines such as triphenylphosphine
  • halosilanes such as tetrachlorosilane
  • X 1 is carboxy
  • the corresponding ammonium salts are primarily formed, which can be obtained by heating or treating with suitable dehydrating agents, such as carbodiimides, for example N, N'-di-lower alkyl or N, N'-dicycloalkyl-carbodiimide, such as N, N'-diethyl -, N, N'-diisopropyl or N, N'-dicyclohexyl-carbodiimide, advantageously with the addition of N-hydroxysuccinimide or optionally, for example substituted by halogen, lower alkoxy or lower alkyl, 1-hydroxy-benzotriazole or N-hydroxy-5- norbornene-2,3-carboxamide, and N, N-carbonyldiimidazole, can be dehydrated.
  • suitable dehydrating agents such as carbodiimides, for example N, N'-di-lower alkyl or N, N'-dicycloalkyl-carbodiimi
  • the corresponding 1-isoureidocarbonyl compounds can also be formed as intermediates.
  • water-binding condensation agents may further N - Etoxycarbon- yl-2-ethoxy-1,2-dihydroquinoline, Phosphorylcyanamide or azides, such as diphenylphosphoryl azide or Diethylphosphorylcyanamid, triphenylphosphine - disulfide or 1-lower alkyl-2-halogeno-piperidinium halides, such as 1 -Methyl-2-chloro-pyridinium iodide can be used.
  • the N-acylation is carried out in a manner known per se, for example in the absence or, usually, in the presence of a suitable solvent or diluent or a corresponding mixture, with cooling, at room temperature or with heating, e.g. in a temperature range from about -20 ° C to about 150 ° C, preferably from about 0 ° C to about 100 ° C, and if necessary in a closed vessel, optionally under pressure and / or in an inert gas atmosphere.
  • the starting materials used in this process variant are partly. known or can be prepared by methods known per se.
  • the preparation of compounds of the formula (IIa) in which X 1 is optionally additionally activated vinyloxycarbonyl can be carried out, for example, by transesterification of a lower alkyl ester with vinyl acetate (method of the activated vinyl ester), by reaction of the free acid of compounds of the formula (IIa) with lower alkoxyacetylene (for example Ethoxyacetylene method) or, analogously to the Woodward method, with a 1,2-oxazolium salt.
  • Compounds of the formula (IIa) which may have substituted phenoxy- or thiophenoxycarbonyl can be carried out, for example, starting from the free acid by the carbodiimide method by reaction with the corresponding (thio) phenol.
  • compounds of the formula (IIa) in which X 1 is activated methoxycarbonyl or 1,1- or 1,3-disubstituted 2-isoureidocarbonyl for example by reaction with a halogen such as Chloroacetonitrile (cyanomethyl ester method) or with a carbodiimide or cyanamide (carbodiimide or cyamide method) can be obtained.
  • a halogen such as Chloroacetonitrile (cyanomethyl ester method) or with a carbodiimide or cyanamide (carbodiimide or cyamide method
  • N-alkyleneaminooxycarbonyl or N-imido-oxycarbonyl compounds of the formula (IIa) can be carried out, for example, when using the free acid of the formula (IIa) from corresponding N-hydroxy compounds with the aid of carbodiimides using the activated N-hydroxyester method respectively.
  • Azidocarbonyl compounds of the formula (IIa) can be obtained, for example, by treating corresponding hydrazides with nitrous acid (azide method).
  • azide method For the preparation of compounds of formula (IIa) wherein X is l-imidazolyl optionally substituted 1-carbonyl, or l-Pyrazolylcarbonyl means are employed, the free acid of formula (IIa), for example with di- (1-imidazolyl) carbonyl (imidazolide Method) or the hydrazide in question, for example with a corresponding 1,3-diketone (pyrazolide method).
  • the starting material of the formula (IIb), in which X represents the carbonyl group can be obtained, for example, by using a compound of the formula Ar 2 -H (IIc) with the piperidine-4-carboxylic acid or a reactive derivative thereof analogously to a Friedel-Crafts Acylation in the presence of a Lewis acid.
  • the compound of the formula thus obtainable can be converted, for example by treatment with a compound of the formula Hal-alk-NH 2 (IIe), in which Hal is halogen, such as bromine, for example in the presence of a base, into the corresponding compound of the formula (IIb).
  • the reduction of the carbonyl group X to the hydroxymethylene group X can, starting from compounds of the formula (IId) or (IIb), for example with the aid of a suitable metal hydride, for example lithium aluminum hydride or sodium borohydride, and the reductive conversion of the carbonyl via the hydroxymethylene group into the methylene group X for example by catalytic hydrogenation in the presence of a hydrogenation catalyst.
  • a suitable metal hydride for example lithium aluminum hydride or sodium borohydride
  • Reactive esterified hydroxy X 5 means, in particular, hydroxy esterified with a strong inorganic acid or organic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy, optionally, for example, substituted by halogen, lower alkanesulfonyloxy, for example methane or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or optionally, for example, substituted by lower alkyl or halogen, benzenesulfonyloxy, for example p-bromophenyl- or p-toluenesulfonyloxy, optionally, for example by halogen, substituted lower alkanoyloxy, such as acety
  • the condensation (N-alkylation) according to the process is carried out in a manner known per se, if necessary in the presence of a base.
  • bases which can be used are alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines.
  • Examples include sodium hydroxide, hydride, amide, potassium tert-butoxide, carbonate, lithium triphenylmethylide, diisopropylamide, potassium 3- (aminopropyl) amide, bis (trimethylsilyl) amide, dimethylaminonaphthalene, di - or triethylamine, or ethyl-diisopropylamine, N-methyl-piperidine,
  • benzyl-trimethyl-ammonium hydroxide 1,5-diaza-bicyclo [4.3.0] non-5-ene (DBN) and 1,8-diaza-bicyclo [5.4.0] undec-7-ene (DBU) called, further phosphines, such as triphenylphosphine, or halosilanes, such as tetrachlorosilane.
  • the N-alkylation is carried out, for example, in the absence or, usually, the presence of a suitable solvent or diluent or a corresponding mixture, at room temperature or with heating, e.g. in a temperature range from about 0 ° C to about 200 ° C, preferably between room temperature and about 150 ° C, and if necessary in a closed vessel, optionally under pressure and / or under inert gas.
  • the starting materials used in this process variant are partly. known or can be prepared by methods known per se.
  • starting materials of the formula (IIIa) in which X 2 is hydrogen and X 3 represents a group of the formula -alk-X 5 can be obtained by, for example, from a carboxylic acid of the formula R-Ar 1 -COOH (IIId) or a reactive acid derivative, in particular a carboxylic acid halide, is assumed and treated with an amine of the formula X 5 -alk-NH 2 (IIIe).
  • Starting materials of the formula (IIIa) in which X 2 and X 3 together represent alk ', where alk' is 2- to 3-membered alkylene having 2 to and 7 carbon atoms, in particular ethylene can be prepared, for example, by a corresponding aziridine or azetidine with a compound of the formula (IIId) or a reactive acid derivative thereof, for example in the presence of a base, for example triethylamine, N-acylated.
  • Starting materials of the formula (IIIa) in which X 2 and X3 are hydrogen can be obtained, for example, from corresponding compounds of the formula (IIId) or their reactive derivatives by reaction with ammonia.
  • Starting material of the formula (IIIc) can be obtained by, for example, compounds of the formulas in the presence of a customary for N-alkylation, for example one of the bases mentioned above, such as pyridine, with elimination of one equivalent of HX S.
  • a customary for N-alkylation for example one of the bases mentioned above, such as pyridine
  • HX S one equivalent of HX S
  • concentration ratios the N-alkylation with elimination of a further equivalent of HX 5 can lead directly to corresponding target compounds of the formula (I) in situ.
  • compounds of the formula (IIIg) or their salts can be obtained, for example, by adding a compound of the formula (IIId) or a reactive acid derivative thereof with an excess of a compound of the formula H 2 N-alk-NH 2 (IIIh) amid normal conditions.
  • Compounds of the formula (IIIi) can, for example, by reacting a compound of the formula X6-CH2 CH 2 -CH 2 -CO-Ar 2 (IIIj), in which X 6 represents, for example, alkoxy, with base catalysis, for example in the presence of sodium amide, with ethylene oxide and subsequent cleavage of the ether.
  • the ether cleavage can be carried out, for example, using a Lewis acid such as boron trifluoride or a strong hydrohalic acid such as bromine. or hydroiodic acid.
  • a hydrohalic acid which is used in excess, compounds of the formula (IIIi) can be obtained in which X is the carbonyl group and X 5 is halogen. If desired, the carbonyl group X can be reductively converted into the hydroxymethylene or methylene group in the customary manner.
  • bases which can be used are alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines.
  • Examples include sodium hydroxide, hydride, amide, potassium tert-butoxide, carbonate, lithium triphenylmethylide, diisopropylamide, potassium 3- (aminopropyl) amide, bis (trimethylsilyl) amide, dimethylaminonaphthalene, di - or triethylamine, or ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo [4.3.o] non-5-ene (DBN) and 1,8-diaza- called bicycloC5.4.0] undec-7-ene (DBU), also phosphines, such as triphenylphosphine, or halosilanes, such as tetrachlorosilane.
  • phosphines such as triphenylphosphine, or halosilanes, such as tetrachloros
  • the reaction is carried out in a manner known per se, for example in the absence or, usually, the presence of a suitable solvent or diluent or a corresponding mixture, with cooling, at room temperature or with heating, e.g. in a temperature range from about -20 ° C to about 200 ° C, preferably between room temperature and about 150 ° C, and if necessary in a closed vessel, optionally under pressure and / or under inert gas.
  • the starting materials used in this process variant are partly. known or can be prepared by methods known per se.
  • starting materials of the formula (IVa) are accessible by starting from a carboxylic acid of the formula R-Ar 1 -COOH (IIId) or a reactive acid derivative, in particular an acid halide, and initially with an amine of the formula X 5 - alk'-NH 2 (IVc), in which X 5 represents reactive esterified hydroxy, and then the resulting carboxamide of the formula wherein X 2 is hydrogen and X 3 is a group of the formula -alk'-X 5 , treated with a base, for example triethylamine or ethyl-diisopropylamine.
  • a base for example triethylamine or ethyl-diisopropylamine.
  • a radical X 7 which can be converted into R represents, for example, the diazonium grouping of the formula -N 2 A, in which A is the anion of a strong protonic acid, for example an anion of a mineral acid or complex metallic acid, such as chloride, perchlorate, sulfate, tetrafluoroborate or Hexachloroantimonate.
  • A is the anion of a strong protonic acid, for example an anion of a mineral acid or complex metallic acid, such as chloride, perchlorate, sulfate, tetrafluoroborate or Hexachloroantimonate.
  • substitution of the diazonium group X 7 in compounds of the formula (V) by hydroxy can be carried out analogously to the "phenol boil" in aqueous medium, while the treatment of the diazonium salt of the formula (V) with an aliphatic alcohol, in particular with a lower alkanol, to give compounds of the formula (I) in which R is hydroxy etherified with an aliphatic alcohol.
  • X in compounds of the formula (V) can be replaced by chlorine, bromine or iodine, for example by reaction with corresponding halides, such as alkali metal halides.
  • the anion A ⁇ is the halide corresponding to the respective halogen atom.
  • the reaction can, for example, be catalyzed by Cu (I) ions analogously to the Sandmeyer reaction, by copper powder in accordance with the Gattermann reaction or by Cu (II) ions based on the Körner-Contardi reaction.
  • the group X 7 can be substituted in a manner known per se, if necessary in the presence of a solvent or diluent, at reduced or elevated temperature, for example in a range from about 40 ° to about 120 ° C., and / or in a closed vessel .
  • the amino group can be converted into the corresponding ionic group X 7 in a manner known per se by customary diazotization, for example using nitrous acid or a nitrite in the presence of an acid.
  • a radical X 7 which can be converted into R can furthermore stand for an acyloxy radical derived from an organic carboxylic acid, which may mean, for example, lower alkanoyloxy or aroyl- such as optionally substituted benzoyloxy, for example substituted by halogen or aryl.
  • an acyloxy radical derived from an organic carboxylic acid which may mean, for example, lower alkanoyloxy or aroyl- such as optionally substituted benzoyloxy, for example substituted by halogen or aryl.
  • compounds of the formula (I) can be obtained, for example, by reaction with a reactive ester of an aliphatic alcohol, for example with a lower alkyl halide or sulfonate, in which R is hydroxy etherified with an aliphatic alcohol. It is advantageous to work in the presence of a base. In the course of this reaction, hydroxy groups esterified with an organic carboxylic acid as substituents of the aromatic radicals Ar or Ar 2 can simultaneously be converted into hydroxy groups etherified with an aliphatic alcohol.
  • a radical X 7 which can be converted into R can furthermore, for example, be protected by a hydroxyl protective group usually used in the relevant literature, this being, for example, 1-aryl-lower alkoxycarbonyloxy, such as optionally substituted in the phenyl ring, for example by halogen, benzyloxycarbonyloxy, 1-aryl-lower alkkoxy, as appropriate in the phenyl part, for example substituted by halogen or lower alkoxy, benzyloxy or silyloxy, such as optionally substituted tri-lower alkylsilyloxy.
  • a hydroxyl protective group usually used in the relevant literature, this being, for example, 1-aryl-lower alkoxycarbonyloxy, such as optionally substituted in the phenyl ring, for example by halogen, benzyloxycarbonyloxy, 1-aryl-lower alkkoxy, as appropriate in the phenyl part, for example substituted by halogen or lower alkoxy, benz
  • Corresponding preferred radicals X 7 are, for example, benzyl-, 2- or 4-bromobenzyloxycarbonyloxy, benzyloxy, 3-bromo, 2,6-dichloro- or 4-methoxybenzyloxy or trimethylsilyloxy.
  • radicals X 7 can be converted in a known manner, for example by hydrolysis, acidolysis or reduction in the hydroxy R.
  • the hydrolytic splitting off of the hydroxyl protective group can optionally be carried out in the presence of a base or acid which supports the hydrolysis, alkali metal or alkaline earth metal hydroxides or carbonates being suitable as bases, and inorganic or organic protonic acids being suitable as acids.
  • 1-Aryl-lower alkoxycarbonyloxy or silyloxy radicals are preferably converted into hydroxy by hydrolysis.
  • strong acids such as mineral acids, e.g. Hydrohalic acids, perchloric acid, optionally suitably substituted lower alkane carboxylic acids or sulfonic acids, such as optionally substituted benzenesulfonic acids, or mixtures thereof.
  • Preferred acids are e.g. Hydrofluoric acids, hydrobromic acid / glacial acetic acid or trifluoroacetic acid.
  • Groups correspondingly convertible into hydroxy R are, for example, 1-aryl-lower alkoxycarbonyloxy or 1-aryl-lower alkoxy.
  • residues can also be reductive, e.g. by hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst or 1-aryl-lower alkoxycarbonyloxy additionally converted reductively by metal systems of metal component and a hydrogen-supplying component, such as sodium / ammonia, into hydroxy.
  • a hydrogenation catalyst or 1-aryl-lower alkoxycarbonyloxy additionally converted reductively by metal systems of metal component and a hydrogen-supplying component, such as sodium / ammonia, into hydroxy.
  • the starting material of formula (V), wherein X 7 represents an acyloxy radical or protected hydroxy can be obtained by, for example, a compound of the formula condensed with a compound of formula (IIa) in analogy to the manner given under variant a).
  • a compound according to the invention which is obtainable in accordance with the process or in another way can be converted into another compound according to the invention in a manner known per se.
  • the hydroxyl group with an organic carboxylic acid such as Lower alkane carboxylic acid
  • esterify is carried out in a manner known per se, for example by treatment with the desired carboxylic acid or a reactive derivative, for example acid anhydride or halide, if necessary in the presence of an acid such as a protonic acid, for example.
  • an acid such as a protonic acid, for example.
  • esterification can also take place in the presence of a base, such as an alkali metal hydroxide, carbonate or an amine or a cyclic nitrogen base, or a water-binding agent, such as a conventional carbodiimide.
  • a base such as an alkali metal hydroxide, carbonate or an amine or a cyclic nitrogen base
  • a water-binding agent such as a conventional carbodiimide.
  • the hydroxy group can be removed by solvolysis, e.g. with the help of base catalysis.
  • the appropriate reactions can be carried out with cooling or heating, e.g. in a temperature range from about 0 ° to about 100 ° C, in the presence or absence of a solvent or diluent, under inert gas and / or under pressure and, if appropriate, in a closed vessel.
  • a hydroxy-containing compound according to the invention can be etherified by methods known per se.
  • the etherification can be carried out, for example, with an alcohol, such as optionally substituted lower alkanol, or a reactive ester thereof.
  • Suitable reactive esters of the desired alcohols are, for example, those with strong inorganic or organic acids, such as corresponding halides, sulfates, lower alkanesulfonates or optionally substituted benzenesulfonates, for example chlorides, bromides, iodides, methane, benzene or p-toluenesulfonates Consider.
  • the etherification can take place, for example, in the presence of a base, an alkali metal hydride, hydroxide, carbonate or a basic amine.
  • corresponding ethers such as lower alkoxy compounds, for example by means of strong acids, such as mineral acids, for example the hydrohalic acids, hydrobromic or hydroiodic acid, which can advantageously be in the form of pyridinium halides, or can be cleaved by means of Lewis acids, for example halides of elements of the 3rd main group or the corresponding subgroups.
  • a compound according to the invention which has a hydroxy lower alkyl radical the hydroxy group, e.g. by treatment with a suitable halogenating agent, e.g. Thionyl chloride, in halogen, e.g. Chlorine.
  • a suitable halogenating agent e.g. Thionyl chloride
  • the aryl group Ar or Ar 2 has, for example, a cyano group as a substituent
  • this can, for example, hydrolytically, preferably under acidic or basic conditions, for example in the presence of an alkali metal hydroxide, and, if desired, in the presence of hydrogen peroxide in an aqueous-alcoholic solvent the carbamoyl group can be transferred.
  • the corresponding reactions can, if necessary, with cooling or heating, for example in a temperature range from about 0 ° to about 150 ° C, occasionally also at higher temperatures, in the presence or absence of a solvent or diluent, under inert gas and / or under Pressure and possibly carried out in a closed vessel.
  • radicals Ar 1 or Ar 2 have cyano as substituents in compounds according to the invention, this can be converted, for example by treatment with an alcohol, for example lower alkanol, in the presence of an acid, for example hydrochloric acid, for example into alkoxycarbonyl.
  • an alcohol for example lower alkanol
  • an acid for example hydrochloric acid
  • such a group can be used, for example, by means of hydrolysis, for example in the presence of a convert basic agents, such as an inorganic base, for example an alkali metal or alkaline earth metal, for example sodium, potassium or calcium hydroxide, or an acidic agent, such as a mineral acid, into a free carboxy group.
  • a convert basic agents such as an inorganic base, for example an alkali metal or alkaline earth metal, for example sodium, potassium or calcium hydroxide
  • an acidic agent such as a mineral acid
  • Compounds of the formula (I) in which Ar 1 or Ar have an esterified carboxy group as substituents can be obtained by transesterification, for example by treatment with an alcohol, usually a higher alcohol than that corresponding to the esterified carboxy group in the starting material, in the presence of a suitable transesterification agent , such as a basic agent, for example an alkali metal lower alkanoate, lower alkanolate or cyanide, such as sodium acetate, methoxide, ethylate, tert-butanolate or cyanide, or a suitable acidic agent, optionally with removal of the alcohol formed, convert it into other ester compounds of the formula (I), for example by distillation.
  • a suitable transesterification agent such as a basic agent, for example an alkali metal lower alkanoate, lower alkanolate or cyanide, such as sodium acetate, methoxide, ethylate, tert-butanolate or cyanide, or a suitable acidic
  • activated esters of formula (I) in which Ar 1 or Ar 2 have an activated esterified carboxy group as substituents (see below), and this by treatment with one alcohol, such as a lower alkanol, into another Convert esters.
  • compounds of the formula (I) which have a free carboxyl group can be reacted with urea at elevated temperatures, for example at 200-240 ° C., with a formamide, for example dimethylformamide, in the presence of a suitable condensing agent, such as phosphorus pentoxide, at elevated temperatures , or with an amine in the presence of a suitable condensing agent, such as a carbodiimide, for example N, N'-diethylcarbodiimide, also a phosphine, such as triphenylphosphine (for example together with bis-2-pyridyl disulfide), or a silane, such as trichlorosilane (eg together with pyridine), and the corresponding amide compounds of the formula (I) in which Ar 1 or Ar 2 contain an amidated carboxy group as substituents are obtained.
  • a suitable condensing agent such as phosphorus pentoxide
  • an amine in the presence of a suitable con
  • M an can also first convert this into a reactive derivative, such as an anhydride, including a mixed anhydride, such as an acid halide, e.g. eg by Behan yours with a thionyl halide, e.g. -chloride), or an anhydride with a formic acid ester, e.g. -lower alkyl ester (e.g.
  • a salt such as an ammonium or alkali metal salt
  • a halogen such as chloroformic acid ester, such as lower alkyl ester
  • Convert esters such as a cyanomethyl, nitrophenyl, for example 4-nitrophenyl or polyhalophenyl, for example pentachlorophenyl ester (for example by treatment with a corresponding hydroxy compound in the presence of a suitable condensing agent such as N, N'-dicyclohexyl-carbodiimide), and then reacting such a reactive derivative with ammonia (optionally in derivatized form) or an amine and thus obtaining amide compounds of the formula (I) in which Ar 1 or Ar 2 have an amidated carboxy group as substituents.
  • a suitable condensing agent such as N, N'-dicyclohexyl-carbodiimide
  • an activated ester such as a 4-nitrophenyl ester
  • a compound of the formula I having a carboxy group can first be reacted with a 1-unsubstituted imidazole and the resulting 1-imidazolylcarbonyl compound reacted with the ammonia or the amine.
  • other non-activated esters such as lower alkyl esters of compounds of the formula (I) in which Ar 1 or Ar 2 have substituents, for example lower alkoxycarbonyl, can also be reacted with ammonia or amines.
  • the respective amino group can be mono- or disubstituted in the manner given above under variant b).
  • primary or secondary amino groups can be reductively alkylated analogously to the Leuckart - Wallach (or Eschweiler-Clarke) reaction from carbonyl compounds, for example using formic acid as a reducing agent.
  • X represents the carbonyl group
  • this can be achieved, for example, by reduction, for example by treatment with a suitable, optionally complex hydride, such as a hydride formed from an element of the 1st and 3rd main group of the PSE, for example sodium borohydride or sodium cyanoborohydride, are converted into the hydroxymetylene group X:.
  • a suitable, optionally complex hydride such as a hydride formed from an element of the 1st and 3rd main group of the PSE, for example sodium borohydride or sodium cyanoborohydride
  • the hydroxymethylene group X in turn can be reduced to the methylene group, for example by reduction, for example with hydrogen using a hydrogenation catalyst.
  • X represents the carbonyl group
  • this can be, for example, in the presence of an acid, such as mineral acid, e.g. Sulfuric or hydrochloric acid, or sulfonic acid, e.g. p-toluenesulfonic acid, with an alcohol such as lower alkanol or lower alkanediol, e.g. Ethanol or glycol, acetalized.
  • an acid such as mineral acid, e.g. Sulfuric or hydrochloric acid, or sulfonic acid, e.g. p-toluenesulfonic acid
  • an alcohol such as lower alkanol or lower alkanediol, e.g. Ethanol or glycol
  • Acetalized carbonyl X can e.g. vice versa by acids, e.g. of the type mentioned above, are hydrolyzed.
  • Suitable oxidizing agents for the oxidation to the sulfoxide stage are, for example, inorganic peracids, such as peracids from mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as corresponding percarbonic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenesulfonic acid, or mixtures of hydrogen peroxide and acids, for example a mixture of hydrogen peroxide with acetic acid.
  • inorganic peracids such as peracids from mineral acids, for example periodic acid or persulfuric acid
  • organic peracids such as corresponding percarbonic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenesulfonic acid
  • mixtures of hydrogen peroxide and acids for example a mixture of hydrogen peroxide with acetic acid.
  • the oxidation is often carried out in the presence of suitable catalysts, suitable acids, such as optionally substituted carboxylic acids, e.g. Acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of subgroup VII, e.g. Vanadium, molybdenum or tungsten oxide are to be mentioned.
  • suitable acids such as optionally substituted carboxylic acids, e.g. Acetic acid or trifluoroacetic acid
  • transition metal oxides such as oxides of elements of subgroup VII, e.g. Vanadium, molybdenum or tungsten oxide are to be mentioned.
  • the oxidation is carried out under mild conditions, e.g. at temperatures from about -50 ° to about + 100 ° C.
  • the oxidation to the sulfone stage can also be carried out with nitrous oxide as a catalyst in the presence of oxygen at low temperatures, as can the direct oxidation of the lower alkylthio to the lower alkanesulfonyl.
  • the oxidizing agent is usually used in excess.
  • an aromatic ring (Ar 1 or Ar 2 ) has a hydrogen atom as a substituent, this can be replaced with a halogen atom using a halogenating agent in a conventional manner, for example with bromine, hypobromic acid, acyl hypobromites or other organic bromine compounds, for example N-bromosuccinimide.
  • a halogenated hydrocarbon such as chloroform
  • the cyano group can be introduced into the ring Ar, for example by reacting a halogen atom, especially iodine or bromine, by reaction with a cyano compound such as an alkali metal cyanide, e.g. Potassium cyanide, or especially with Cu (I) cyanide, preferably with heating, e.g. up to about 60 ° to about 250 ° C, in the presence or absence of a solvent or diluent, or advantageously under inert gas, substituted by the cyano group.
  • a cyano compound such as an alkali metal cyanide, e.g. Potassium cyanide, or especially with Cu (I) cyanide
  • aryl radical Ar 1 or Ar 2 in the compounds according to the invention contains an amino group
  • this can be diazotized in a conventional manner, for example by treatment with a nitrite, for example sodium nitrite, in the presence of a suitable protonic acid, for example mineral acid, the reaction temperature advantageously being below about 5 ° C is kept.
  • a nitrite for example sodium nitrite
  • a suitable protonic acid for example mineral acid
  • the diazonium group available in salt form can be substituted by analogous processes, for example as follows: by the hydroxyl group analogous to the phenol boil in the presence of water; by an alkoxy group by treating with an equivalent alcohol, whereby energy must be supplied; by the fluorine atom analogous to the Schiemann reaction in the thermolysis of corresponding diazonium tetrafluoroborates; by the halogen atoms chlorine, bromine or iodine and the cyano group analogous to the Sandmeyer reaction in the reaction with corresponding Cu (I) salts, first with cooling, for example to about below 5 ° C., and then with heating, for example to about 60 ° to about 150 ° C.
  • the compounds according to the invention have a nitro group in the aryl radical Ar or Ar 2 , this can be reduced to the amino group in a manner known per se, for example by catalytic hydrogenation.
  • an aromatic ring Ar 1 or Ar can be alkylated, for example, with a lower alkanol or a lower alkyl halide or a phosphoric acid lower alkyl ester in the presence of Lewis acids (Friedel-Crafts alkylation).
  • a compound of formula (I) in which an aromatic ring contains bromine for example, the bromine can be replaced by lower alkyl by reaction with a lower alkyl bromide in the presence of an alkali metal.
  • an aromatic ring contains a hydrogen atom as a substituent
  • this can be exchanged for an acyl group in a manner known per se.
  • the insertion of the acyl group can be carried out analogously to Friedel-Crafts acylation (cf. G.A. Olah, Friedel-Crafts and Related Reactions, Vol. I, Interscience, New York, 1963-1965), e.g. by reacting a reactive functional acyl derivative, such as a halide or anhydride, an organic carboxylic acid in the presence of a Lewis acid, such as aluminum, antimony (III) - or - (V) -, iron (III) -, zinc (II) chloride or boron trifluoride.
  • a reactive functional acyl derivative such as a halide or anhydride
  • an organic carboxylic acid in the presence of a Lewis acid, such as aluminum, antimony (III) - or - (V) -, iron (III) -
  • the compounds of the formula (I) contain unsaturated radicals, such as lower alkenyl or lower alkadienyl groups, these can be converted into saturated radicals in a manner known per se.
  • unsaturated radicals such as lower alkenyl or lower alkadienyl groups
  • these can be converted into saturated radicals in a manner known per se.
  • noble metals or their derivatives, for example oxides are suitable, such as nickel, Raney nickel, palladium, platinum oxide, which can optionally be applied to support materials, for example carbon or calcium carbonate.
  • the hydrogenation can preferably be carried out at pressures between 1 and about 100 at and at a temperature between about -80 * and about 200 ° C., especially between room temperature and about 100 ° C.
  • the reaction is conveniently carried out in a solvent such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkane carboxylic acid, for example acetic acid.
  • a solvent such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkane carboxylic acid, for example acetic acid.
  • the invention particularly relates to the methods described in the examples.
  • starting materials mentioned have basic centers, e.g. acid addition salts are also formed, while starting materials with acidic groups e.g. Form salts with bases.
  • the starting materials can be used in free form or as salts or the compounds according to the invention with salt-forming properties can be obtained in free form or in the form of salts.
  • Acid addition salts obtained in this way can be prepared in a manner known per se, e.g. by treatment with a base such as an alkali metal hydroxide into the free compounds or e.g. can be converted to other salts by treatment with suitable acids or derivatives thereof.
  • a base such as an alkali metal hydroxide
  • Free compounds obtained with salt-forming basic properties can e.g. by treatment with acids or corresponding anion exchangers, can be converted into their salts.
  • the free compounds or their salts are to be understood as meaningful and expedient, if appropriate, also the corresponding salts or free compounds. Salts which are unsuitable for pharmaceutical uses are also included, since these can be used, for example, for the isolation or purification of free compounds according to the invention and their pharmaceutically usable salts.
  • the compounds according to the invention including salts of corresponding salt-forming compounds, can also be obtained in the form of their hydrates, or their crystals can e.g. include the solvent used for crystallization.
  • the new compounds can, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures.
  • Diastereomer mixtures and racemate mixtures obtained can be separated into the pure isomers, diastereomers or racemates in a known manner on account of the physico-chemical differences in the constituents, for example by chromatography on chiral adsorbents and / or fractional crystallization.
  • Racemates obtained can furthermore be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, a Enantiomeres is complexed, or by conversion into diastereomeric salts or esters, for example by reacting a basic end product racemate with an optically active acid or an optically active carboxylic acid or a reactive derivative forming salts with the racemic base, and separation of the mixture of diastereomers obtained in this way, for example due to their different solubilities, into the diastereomers from which the desired enantiomer can be released by the action of suitable agents.
  • the more effective enantiomer is advantageously isolated.
  • the invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a derivative or salt and / or its racemates or antipodes or in particular forms under the reaction conditions.
  • the dosage of the active ingredient which is administered alone or together with the usual carrier and auxiliary material, depends on the species to be treated, their age and individual condition and the mode of administration.
  • the single doses are e.g. for mammals with a body weight of approx. 70 kg, depending on the type of disease, individual condition and age, preferably between about 0.5 and 100 mg, e.g. between about 0.7 and 70 mg, e.g. with oral administration.
  • the invention further relates to a process for the preparation of pharmaceutical preparations which contain compounds of the formula (I) or pharmaceutically usable salts of such compounds having salt-forming properties as active ingredients.
  • the pharmaceutical preparations according to the invention are those for enteral, such as peroral or rectal, further for parenteral administration to warm-blooded animals.
  • Corresponding dosage unit forms, in particular for oral administration, e.g. Dragees, tablets or capsules preferably contain from about 1 mg to about 100 mg, in particular from about 1 mg to about 25 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt of a corresponding compound capable of salt formation together with pharmaceutically usable excipients .
  • Suitable carriers are in particular fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as starch paste using, for example, corn, wheat, rice or potato starch, gelatin , Tragacanth, methyl cellulose and / or, if desired, disintegrants, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate
  • binders such as starch paste using, for example, corn, wheat, rice or potato starch, gelatin , Trag
  • Dragee cores can be provided with suitable, optionally gastric juice-resistant, coatings, including concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice -resistant coatings, solutions of suitable cellulose preparations Paraten, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate used. Dyes or pigments can be added to the tablets or dragee coatings, for example for identification or for labeling different doses of active substance.
  • capsules made of gelatin as well as soft, closed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol.
  • the capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.
  • suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.
  • suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.
  • suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added
  • suppositories into consideration consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material; as basic materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.
  • aqueous solutions of an active ingredient in water-soluble form for example a water-soluble salt
  • suspensions of the active ingredient such as corresponding oily injection suspensions
  • suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides
  • viscosity-increasing substances for example sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally stabilizers.
  • compositions of the present invention can be used in a manner known per se, e.g. can be produced by means of conventional mixing, granulating, coating, solution or lyophilization processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, into tablets or dragee cores after adding suitable auxiliaries .
  • Example 1 41.4 g (0.2 mol) of 4- (p-fluorobenzoyl) piperidine are dissolved in 120 ml of dioxane and mixed with 28.3 g (0.1 mol) of N- (2-bromoethyl) -5- added cyano-2-methoxy-benzamide and then stirred for 60 hours at room temperature. The reaction mixture is then mixed with a solution of potassium carbonate and then extracted with methylene chloride. The methylene chloride solution is washed neutral with water and concentrated in a water jet vacuum. A light yellow crystalline product remains, which is slurried in 200 ml of ethanol and stirred for 2 hours.
  • a solution of 26.5 g (0.1 mol) of 5-bromo-4-chloro-2-methoxy-benzoic acid in 150 ml of ethanol is saturated with hydrogen chloride gas and then left to stand for 15 hours. It is then evaporated in a water jet vacuum, the residue is taken up in methylene chloride and extracted with sodium bicarbonate. The methylene chloride solution is dried over magnesium sulfate and then evaporated in a water jet vacuum.
  • 5-bromo-4-chloro-2-methoxy-benzoic acid ethyl ester of mp 79-81 ° remains as residue.
  • Example 6 N- [2- [4- (p-fluorobenzoyl) piperidinyl) ethyl] -2-methoxy-5-trifluoromethylbenzamide hydrochloride, mp 212 ° with decomposition; starting from 41.4 g (0.2 mol) of 4- (p-fluorobenzoyl) piperidine and 32.6 g (0.1 mol) of N- (2-bromoethyl) -2-methoxy-5-trifluoromethyl-benzamide in 180 ml of dioxane.
  • Example 8 24.1 g (0.1 mol) of 2- (5-chloro-2-methoxy-4-methylaminophenyl) -2-oxazoline, 22.8 g (0.11 mol) of 4- (p- Fluorobenzoyl) piperidine and 120 ml of dioxane are heated to boiling in a nitrogen atmosphere for 18 hours. The dark brown solution obtained is evaporated in a water jet vacuum. You get viscous oil that is dissolved in 300 ml of acetone and, with stirring, an ethereal hydrogen chloride solution is added until a congosaic reaction occurs, the product beginning to crystallize out.
  • the starting material is produced as follows:
  • Example 9 In an analogous manner to that described in Example 8, the following is obtained:
  • Example 10 20.2 g (0.1 mol) of N- (5-cyano-2-methoxy-benzoyl) aziridine, 22.8 g (0.11 mol) of 4- (p-fluorobenzoyl) piperidine and 250 ml of toluene are heated to 80 ° for 5 hours with stirring. After cooling, the precipitated 5-cyano-N- [2- [4- (p-fluorobenzoyl) piperidinyl] ethyl] -2-methoxy-benzamide is filtered off and washed with a little toluene, mp. 167-169 °.
  • the starting material is produced as follows:
  • Example 13 To a suspension of 4.1 g (0.01 mole) of 5-cyano-N- [2- [4- (p-fluorobenzoyl) piperidine] ethyl] -2-methoxy-benzamide in 5 0 ml 0.38 g (0.01 mol) of sodium borohydride are added with stirring and the mixture is stirred at room temperature for 1 hour. The clear solution obtained is mixed with 1 ml of acetone and then evaporated in a water jet vacuum. The residue is taken up in methylene chloride and water, the layers are separated in a separating funnel and the organic phase is evaporated after drying over magnesium sulfate.
  • Example 14 To a mixture of 32.3 g (0.1 mol) of N- (2-aminoethyl) -4- (p-fluorobenzoyl) piperidine hydrochloride and 24 g of 3-bromo-4-fluorobenzene zoyl chloride in 250 ml of methylene chloride is added dropwise with stirring and nitrogen atmosphere at -10 ° to 0 ° 45 g (0.35 mol) of diisopropylethylamine. The mixture is then allowed to warm to room temperature and the reaction mixture is kept at this temperature for 4 hours.
  • this base is dissolved in methylene chloride and mixed with ethereal hydrogen chloride solution.
  • the hydrochloride melts at 189-190 °.
  • N- (2-aminoethyl) -4- (p-fluorobenzoyl) piperidine hydrochloride used as the starting material is prepared as follows:
  • N- (2-aminoethyl) -4- (p-fluorobenzoyl) piperidine hydrochloride is obtained, which melts after recrystallization from methanol at 265 ° with decomposition.
  • the 3-bromo-4-fluoro-benzoyl chloride used as starting material is analogously to Example 3 from 21.9 g (0.1 mol) of 3-bromo-4-fluorobenzoic acid (produced according to J. Indian Chem. Soc. 21, 115 (1944 )) and 10 ml of thionyl chloride.
  • N- (3-cyano-4-methoxy-benzoyl) aziridine mp 176-177 °; starting from 4.52 g (0.105 mol) of aziridine, 12.9 g (0.1 mol) of ethyldiisopropylamine and 19.6 g (0.1 mol) of 3-cyano-4-methoxy-benzoyl chloride in 150 ml of methylene chloride.
  • N- [2- [4- (p-fluorobenzoyl) piperidinyl] ethyl] -2-methoxy-5-methanesulfonylbenzamide hydrochloride mp 163-164 °; starting from 6.5 g (0.02 mol) of N- (2-aminoethyl) -4- (p-fluorobenzoyl) piperidine hydrochloride, 4.99 g (0.02 mol) of 2-methoxy-5-methanesulfonyl- benzoyl chloride and 9 g (0.07 mol) of ethyldiisopropylamine in 50 ml of methylene chloride.
  • N- (cyanomethyl) -4- (p-fluorobenzyl) piperidine hydrochloride are concentrated in 300 ml of glacial acetic acid and 7 ml. Hydrochloric acid dissolved and hydrogenated together with 1 g of platinum oxide in a hydrogen atmosphere. After 4 hours, the theoretical amount of 2.25 l of hydrogen is taken up. The catalyst is then filtered off with suction and the filtrate is concentrated to about 30 ml in a water jet vacuum. The resulting crystal slurry is mixed with 5 ml of isopropanol and 10 ml of ether and suction filtered. This gives the N- (2-aminoethyl) -4- (p-fluorobenzyl) piperidine hydrochloride, which melts at 171-173 ° after recrystallization from ethanol-ether.
  • Example 20 6.69 g (0.015 mol) of S-cyano-N- [2- [4- (p-fluorobenzoyl) piperidinyl] ethyl] -2-methoxybenzamide hydrochloride are dissolved in 50 ml of methanol and 50 ml Toluene suspended. While stirring and cooling, hydrogen chloride gas is introduced at 0 ° until a clear solution is formed. Then 100 ml of ice water are slowly run in and the mixture is then heated to 70 "for a further hour. After cooling, it is carefully adjusted to weakly alkaline with potash and the mixture thus obtained is extracted with methylene chloride.
  • Example 21 6.69 g (0.015 mol) of 5-cyano-N- [2- [4- (p-fluorobenzoyl) piperidinyl] ethyl] -2-methoxy-benzamide hydrochloride are dissolved in 60 ml of 85X sulfuric acid under a nitrogen atmosphere dissolved and left for 7 days at room temperature. Then this solution is added dropwise with stirring to a mixture of 130 ml of conc. Ammonia and 200 g ice, forming a white precipitate. This is filtered off and recrystallized from methylene chloride-methanol. The 5-carbamoyl-N- [2- [4- (p-fluorobenzoyl) piperidinyl] ethyl-2-methoxy-benzamide of mp 236-238 ° is thus obtained.
  • Example 22 2.14 g (0.01 mol) of 2-methoxy-5-methanesulfinylbenzoic acid and 3.23 g (0.01 mol) of N- (2-aminoethyl) -4- (p-fluorobenzoyl) piperidine dihydrochloride are dissolved in 10 ml of dimethylformamide and mixed with 2.13 g (0.021 mol) of triethylamine. With stirring and a nitrogen atmosphere, 3.26 g (0.0105 mol) of triphenyl phosphite are added and the reaction mixture obtained is heated at 85-90 ° for 2.5 hours.
  • Example 25 26.8 g (0.11 mol) of 4- (p-fluorobenzoyl) piperidine hydrochloride, 34.5 g (0.25 mol) of potash and 25.3 g (0.1 mol) of N- ( 3-chloropropyl) -5-cyano-2-methoxy-benzamide are heated to boiling together with 0.5 g of potassium iodide in 250 ml of ethanol with stirring for 15 hours. Then the reaction mixture is evaporated in a water jet vacuum and the residue is taken up in ether, a little methylene chloride and water. After the aqueous phase has been separated off, the basic fractions are separated from the organic phase by shaking out with 2N methanesulfonic acid.
  • the acidic extracts are adjusted to pH 9 with sodium hydroxide solution and then extracted with methylene chloride.
  • the methylene chloride solution is washed neutral with water, dried over magnesium sulfate and evaporated in a water jet vacuum.
  • the crude product thus obtained is subjected to flash chromatography, the chloroform-methanol 49: 1 fractions providing the desired 5-cyano-N- [3- [4- (p-fluorobenzoyl) piperidinyl] propyl] -2-methoxy - Elute benzamide from mp. 133-135 °.
  • Example 26 20.8 g (0.1 mol) of 2- (2,6-dimethoxypyridinyl) -2-oxazoline, 22.8 g (0.11 mol) of 4- (p-fluorobenzoyl) piperidine , 12.9 g (0.1 mol) of diisopropylethylamine and 120 ml of dioxane are stirred heated to 80 ° for 16 hours. Then methylene chloride and water are added and the pH is adjusted to 9 with saturated potassium carbonate solution. The layers are separated in a separatory funnel and the organic phase is evaporated in a water jet vacuum.
  • the free base is dissolved in a little methylene chloride and then, with stirring, an ethereal methanesulfonic acid solution is added until the reaction is weakly congo acidic, the N- [2- [4- (1-fluorobenzoyl) piperidinyl] ethyl] -2 , 6-nicotinamide methanesulfonate fails.
  • the crude product is recrystallized once from isopropanol. Mp 170-172 °.
  • Example 27 Tablets containing 25 mg of active ingredient, for example 5-cyano-N- [2- [4- (p-fluorobenzoyl) piperidinyl) ethyl] -2-methoxy-benzamide, can be prepared as follows:
  • Example 28 Tablets containing 0.02 g of the methanesulfonic acid salt of 5-cyano-N- [2- [4- (p-fluorobenzoyl) piperidinyl] ethyl] -2-methoxy-benzamide are prepared as follows:
  • Composition for 10,000 tablets
  • a mixture of the active ingredient, the lactose and 194.70 g of potato starch is moistened with an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remaining potato starch, the talc, the magnesium stearate and the colloidal silicon dioxide are mixed in and the mixture is pressed into tablets each weighing 0.1 g, which, if desired, can be provided with partial notches for finer adjustment of the dosage.
  • Capsules containing 0.025 g of the active ingredient e.g. 5-Cyano-N- [2- [4- (p-fluorobenzoyl) piperidinyl] ethyl] -2-methoxybenzamide can be prepared as follows:
  • Composition for 1000 capsules
  • the active ingredient is mixed with the lactose, the mixture is moistened uniformly with an aqueous solution of the gelatin and granulated through a sieve with a mesh size of 1.2-1.5 mm.
  • the granules are mixed with the dried corn starch and talc and 300 mg portions are filled into hard gelatin capsules (size 1).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
EP84810109A 1983-03-09 1984-03-05 Carboxamides, procédé pour leur préparation et préparations pharmaceutiques les contenant Expired EP0124476B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT84810109T ATE35257T1 (de) 1983-03-09 1984-03-05 Carboxamide, verfahren zur herstellung und pharmazeutische praeparate, die diese enthalten.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH125883 1983-03-09
CH1258/83 1983-03-09
CH3925/83 1983-07-18
CH392583 1983-07-18

Publications (2)

Publication Number Publication Date
EP0124476A1 true EP0124476A1 (fr) 1984-11-07
EP0124476B1 EP0124476B1 (fr) 1988-06-22

Family

ID=25687141

Family Applications (1)

Application Number Title Priority Date Filing Date
EP84810109A Expired EP0124476B1 (fr) 1983-03-09 1984-03-05 Carboxamides, procédé pour leur préparation et préparations pharmaceutiques les contenant

Country Status (21)

Country Link
US (1) US4559349A (fr)
EP (1) EP0124476B1 (fr)
KR (1) KR900008674B1 (fr)
AR (1) AR242185A1 (fr)
AU (1) AU583470B2 (fr)
CA (1) CA1273929A (fr)
CY (1) CY1576A (fr)
DD (1) DD220308A5 (fr)
DE (1) DE3472251D1 (fr)
DK (1) DK159420C (fr)
ES (3) ES530358A0 (fr)
FI (1) FI80019C (fr)
HK (1) HK18491A (fr)
HU (1) HU191591B (fr)
IE (1) IE57057B1 (fr)
IL (1) IL71185A (fr)
NO (1) NO164349C (fr)
NZ (1) NZ207428A (fr)
PH (1) PH21416A (fr)
PT (1) PT78212B (fr)
SG (1) SG91490G (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0177078A1 (fr) * 1984-09-12 1986-04-09 Duphar International Research B.V Dérivés d'amines tertiaires spasmolytiques et méthodes pour leur préparation
EP0183190A1 (fr) * 1984-11-23 1986-06-04 Ciba-Geigy Ag Benzamides et les sels
EP0288423A1 (fr) * 1987-04-20 1988-10-26 Schering Aktiengesellschaft Procédé de préparation de sulfonamidobenzamides substitués et un intermédiaire
FR2676226A1 (fr) * 1991-05-03 1992-11-13 Sanofi Elf Nouveaux intermediaires pour la synthese de composes dialkylenepiperidino.
EP0661266A1 (fr) * 1993-12-27 1995-07-05 Toa Eiyo Ltd. Composés cycliques aminés substitués comme 5HT2 antagonistes
US5728835A (en) * 1993-12-27 1998-03-17 Toa Eiyo, Ltd. Substituted cyclic amine compound, production process thereof and pharmaceutical composition for circulatory organ use containing the same
WO2000058305A1 (fr) * 1999-03-26 2000-10-05 Astrazeneca Ab Nouveaux composes
US7265227B2 (en) 2001-07-23 2007-09-04 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
EP1546100A4 (fr) * 2002-08-26 2007-10-31 Sk Corp Nouveaux composes benzoyle piperidine
US7304077B2 (en) 2000-09-04 2007-12-04 Astrazeneca Ab Chemical compounds
US7348341B2 (en) 2000-05-31 2008-03-25 Astrazeneca Ab Chemical compounds

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2581993B1 (fr) * 1985-05-14 1988-03-18 Synthelabo Derives de (benzoyl-4 piperidino)-2 phenyl-1 alcanols, leur preparation et leur application en therapeutique
DE3888727T2 (de) * 1987-06-02 1994-09-01 Ajinomoto Kk Verwendung von Äthylamin-Derivaten als antihypertensive Wirkstoffe.
US4990511A (en) * 1988-08-03 1991-02-05 Takeda Chemical Industries, Ltd. Amide compounds, their production and use
FI97540C (fi) * 1989-11-06 1997-01-10 Sanofi Sa Menetelmä terapeuttisesti käyttökelpoisten, aromaattisesti substituoitujen piperidiini- ja piperatsiinijohdannaisten valmistamiseksi
CA2129995C (fr) * 1992-02-13 2000-04-11 Albert A. Carr Derives thiacycliques de piperidinyle
US6339087B1 (en) 1997-08-18 2002-01-15 Syntex (U.S.A.) Llc Cyclic amine derivatives-CCR-3 receptor antagonists
IL125658A0 (en) 1997-08-18 1999-04-11 Hoffmann La Roche Ccr-3 receptor antagonists
CA2350722A1 (fr) * 1998-11-17 2000-05-25 Leyi Gong Antagonistes iii du recepteur 4-aroyl-piperidin-ccr-3
TR200101397T2 (tr) 1998-11-20 2001-11-21 F.Hoffmann-La Roche Ag Piperidin CCR-3 reseptörü antagonistleri

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013612A2 (fr) * 1979-01-08 1980-07-23 Janssen Pharmaceutica N.V. Dérivés de (pipéridinylalcoyl)quinazoline, procédé pour leur préparation et compositions pharmaceutiques les contenant

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE635597A (fr) * 1962-03-01
US3632767A (en) * 1968-02-12 1972-01-04 Mallinckrodt Chemical Works Treatment of depression with 4-substituted piperidines
US3956296A (en) * 1974-12-11 1976-05-11 A. H. Robins Company, Incorporated 1-Substituted-4-benzylpiperidines
EP0174653A3 (fr) * 1984-09-14 1987-06-16 Ciba-Geigy Ag Dérivés phénylalkyles
EP0181793B1 (fr) * 1984-10-16 1988-07-27 Synthelabo Dérivés de pipéridine, leur préparation et leur application en thérapeutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013612A2 (fr) * 1979-01-08 1980-07-23 Janssen Pharmaceutica N.V. Dérivés de (pipéridinylalcoyl)quinazoline, procédé pour leur préparation et compositions pharmaceutiques les contenant

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0177078A1 (fr) * 1984-09-12 1986-04-09 Duphar International Research B.V Dérivés d'amines tertiaires spasmolytiques et méthodes pour leur préparation
EP0183190A1 (fr) * 1984-11-23 1986-06-04 Ciba-Geigy Ag Benzamides et les sels
EP0288423A1 (fr) * 1987-04-20 1988-10-26 Schering Aktiengesellschaft Procédé de préparation de sulfonamidobenzamides substitués et un intermédiaire
FR2676226A1 (fr) * 1991-05-03 1992-11-13 Sanofi Elf Nouveaux intermediaires pour la synthese de composes dialkylenepiperidino.
EP0661266A1 (fr) * 1993-12-27 1995-07-05 Toa Eiyo Ltd. Composés cycliques aminés substitués comme 5HT2 antagonistes
US5728835A (en) * 1993-12-27 1998-03-17 Toa Eiyo, Ltd. Substituted cyclic amine compound, production process thereof and pharmaceutical composition for circulatory organ use containing the same
WO2000058305A1 (fr) * 1999-03-26 2000-10-05 Astrazeneca Ab Nouveaux composes
JP2002540204A (ja) * 1999-03-26 2002-11-26 アストラゼネカ・アクチエボラーグ 新規化合物
US6518286B1 (en) 1999-03-26 2003-02-11 Astrazeneca Ab Compounds
US6946478B2 (en) 1999-03-26 2005-09-20 Astrazeneca Ab Compounds
US7348341B2 (en) 2000-05-31 2008-03-25 Astrazeneca Ab Chemical compounds
US7304077B2 (en) 2000-09-04 2007-12-04 Astrazeneca Ab Chemical compounds
US7265227B2 (en) 2001-07-23 2007-09-04 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
EP1546100A4 (fr) * 2002-08-26 2007-10-31 Sk Corp Nouveaux composes benzoyle piperidine
AU2003251206B2 (en) * 2002-08-26 2009-05-28 Sk Biopharmaceuticals Co., Ltd. New benzoyl piperidine compounds

Also Published As

Publication number Publication date
KR900008674B1 (ko) 1990-11-26
PT78212B (en) 1986-08-12
FI840867L (fi) 1984-09-10
NO164349B (no) 1990-06-18
DK114684A (da) 1984-09-10
DE3472251D1 (en) 1988-07-28
HK18491A (en) 1991-03-22
ES8800152A1 (es) 1987-10-16
DK159420B (da) 1990-10-15
NO164349C (no) 1990-09-26
PT78212A (en) 1984-04-01
US4559349A (en) 1985-12-17
AU2542484A (en) 1984-09-13
ES8702890A1 (es) 1987-01-16
CY1576A (en) 1991-12-20
PH21416A (en) 1987-10-15
NO840889L (no) 1984-09-10
EP0124476B1 (fr) 1988-06-22
DK114684D0 (da) 1984-02-28
IE57057B1 (en) 1992-04-08
AU583470B2 (en) 1989-05-04
KR840008321A (ko) 1984-12-14
CA1273929A (fr) 1990-09-11
FI840867A0 (fi) 1984-03-05
HU191591B (en) 1987-03-30
ES553050A0 (es) 1987-10-16
ES8602659A1 (es) 1985-12-01
DK159420C (da) 1991-03-11
SG91490G (en) 1991-01-18
IL71185A (en) 1988-06-30
FI80019B (fi) 1989-12-29
FI80019C (fi) 1990-04-10
AR242185A1 (es) 1993-03-31
ES544713A0 (es) 1987-01-16
NZ207428A (en) 1987-03-06
ES530358A0 (es) 1985-12-01
IL71185A0 (en) 1984-06-29
DD220308A5 (de) 1985-03-27
IE840563L (en) 1984-09-09

Similar Documents

Publication Publication Date Title
EP0124476B1 (fr) Carboxamides, procédé pour leur préparation et préparations pharmaceutiques les contenant
EP0004920B1 (fr) Dérivés de la carbazolyl-4-oxypropanolamine, procédés pour leur préparation et médicaments les contenant
DE69013607T2 (de) Pyrazol-Derivate, Verfahren zu deren Herstellung und Anwendung.
EP0104342B1 (fr) Acides triphénylimidazolyloxyalcanoiques et leurs dérivés, procédé de leur préparation et compositions pharmaceutiques les contenant
EP0528762B1 (fr) Acides aminés N-acyl-N-hétérocyclyl- ou naphtyl-alkyl comme angiotensine II antagonistes
EP0435827A2 (fr) Composés diazas
EP0415886A2 (fr) Composés aza
EP0490820A2 (fr) Dérivés biphénylylés
DE69132167T2 (de) Kondensierte benzoxa-ringverbindung, deren herstellung sowie diese enthaltendes arzneimittel
DE3444046A1 (de) N-acylierte diamidderivate saurer aminosaeuren, deren salze, verfahren zur herstellung derselben und anti-ulcus-mittel mit einem gehalt derselben
EP0071935B1 (fr) Composés du 1-phényl-2-aminocarbonylindole, procédé de préparation et intermédiaires et médicaments contenant ces composés
EP0078240A2 (fr) Lactones
EP0116360A1 (fr) Composé de 1-phényl-2-aminocarbonylindole, leur préparation et les médicaments les contenant
DE3347173A1 (de) Neue benzothiazin-derivate, verfahren zu ihrer herstellung, sie enthaltende arzneimittel und deren verwendung
DE3424586A1 (de) 3-aminocarbonylmethoxy-5-phenyl-pyrazol-verbindungen sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
EP0183190B1 (fr) Benzamides et les sels
DE3132915A1 (de) 1,5-diphenylpyrazolin-3-on-verbindungen sowie verfahren und zwischenprodukte zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
EP0389425B1 (fr) Benzothiopyranylamines
DD258812A1 (de) Verfahren zur herstellung neuer ixoxazolderivate
DE2740678A1 (de) 1-amino-2-hydroxy-3-heterocycloxypropane
EP0030030A1 (fr) Dérivés du 2-aminoéthanol, procédés pour leur préparation, préparations pharmaceutiques contenant de tels composés et utilisation de ces dernières
US4521606A (en) 5-Indolyl substituted aminoethanols
DD210266A5 (de) Verfahren zur herstellung von 3-(ureidocyclohexylamino)-propan-1,2-diolderivaten
US4562200A (en) 5(Indolyl) and 5(2,3-dihydroindolyl) substituted aminoethanols and their use as anti-hypertensives
EP0162217A1 (fr) Dérivés de 1,2,4-triazacycloalcadiène

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19840315

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19860423

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

REF Corresponds to:

Ref document number: 35257

Country of ref document: AT

Date of ref document: 19880715

Kind code of ref document: T

REF Corresponds to:

Ref document number: 3472251

Country of ref document: DE

Date of ref document: 19880728

ET Fr: translation filed
ITF It: translation for a ep patent filed
GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
ITTA It: last paid annual fee
EPTA Lu: last paid annual fee
EAL Se: european patent in force in sweden

Ref document number: 84810109.3

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19970123

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19970128

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19970205

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19970206

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19970211

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 19970212

Year of fee payment: 14

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Free format text: CIBA-GEIGY AG TRANSFER- NOVARTIS AG

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19970324

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19970410

Year of fee payment: 14

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19970502

Year of fee payment: 14

NLS Nl: assignments of ep-patents

Owner name: NOVARTIS AG

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980305

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980305

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980305

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980306

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980331

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980331

Ref country code: FR

Free format text: THE PATENT HAS BEEN ANNULLED BY A DECISION OF A NATIONAL AUTHORITY

Effective date: 19980331

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980331

BERE Be: lapsed

Owner name: NOVARTIS A.G.

Effective date: 19980331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19981001

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19980305

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 19981001

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19981201

EUG Se: european patent has lapsed

Ref document number: 84810109.3

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST